Benzoylphenoxy propionic acid, esters thereof and pharmaceutical composition

ABSTRACT

Compounds of the formula ##STR1## in which A is lower alkyl, or a substituted or unsubstituted phenyl, thienyl, furyl, indolyl or thiaindolyl radical, R, X 4  and X 5  are hydrogen or lower alkyl, Y is hydrogen, hydroxy, etherified hydroxy, substituted amino, or N-attached heterocyclyl, X 0  is O or OCH 2  CH 2  O, R&#39; represents hydrogen, lower alkyl or acetyl; and acid-addition salts thereof, are novel and useful in pharmacy as hypolipaemiant, hypocholosterolaemiant and cholagogic agents or in the preparation of such agents.

This is a division, of application Ser. No. 656,711, filed Feb. 9, 1976,now U.S. Pat. No. 4,072,705.

The present invention relates to industrial products which areparticularly useful in therapeutics as active medicaments in thecardiovascular field, in particular as hypolipidaemiant,hypocholesterolaemiant and cholagogic agents. It also relates toprocesses for synthesising these products and their application intherapeutics.

More especially, the invention is directed to:

(1) the compounds of formula II hereinafter, which are new industrialproducts useful in therapeutics;

(2) the compounds of formula I hereinafter, which are particularlyinvolved as intermediates in the synthesis of the compounds of formulaII and which are also useful in therapeutics, and except for someproducts already described in French Patent Nos. 2 035 821 and 2 157853, the compounds of formula I are new products;

(3) the new processes for synthesising compounds of formula I and II;and

(4) the therapeutic application of the new compounds I and II,particularly as hypolipidaemiant, hypocholesterolaemiant and cholagogicagents.

According to the invention the following acids are proposed:p-(alkyl-carbonyl)-, p-(cycloalkyl-carbonyl), p-(aryl-carbonyl)-,p-(heteroarylcarbonyl)-, p-[α-alkyl-α-hydroxy)methyl],p-[(4-cycloalkyl-α-hydroxy)-methyl], p-[(α-aryl-α-hydroxy]methyl)- andp-(heteroaryl-α-hydroxy)methyl)-phenoxyalkylcarboxylic acids and theirderivatives (in particular the derivatives which result from (i)esterification and amidification of the carboxylic acid group, and (ii)esterification and etherification of the α-hydroxy group on the onehand, or conversion of the p-carbonyl group to the acetal group on theother hand), which have the following formulae: ##STR2## in which Arepresents methyl, ethyl, n-propyl, isopropyl, n-butyl ##STR3## [whereX₁, X₂ and X₃ are the same or different and each represents, II, Cl, Br,F, CF₃, NO₂, NH₂, OH, C₁₋₄ alkyl group, C₁₋₄ alkoxy group, benzyloxygroup, acetylamino group, acetoxy group, CHO, COOH, OC(CH₃)₂ COY₁ (whereY₁ is preferably OH or C₁₋₄ alkoxy); X₆ represents O or S; and X₇represents H, Cl, Br]; R, X₄ and X₅, which are identical or different,each represents a hydrogen atom or a C₁₋₄ alkyl group; X₀ is O or OCH₂CH₂ O, Y represents II, OH, OM (where M is a metal or a stoichiometricportion of a metal), a C₁₋₁₂ alkoxy group (whose hydrocarbon radical isstraight-chain or branched), a C₃₋₈ cycloalkyloxy group, a C₁₋₄alkylthio group, a 2,3-dihydroxypropyloxy group, a4-(2,2-dimethyl-1,3-dioxolanyl)-methyleneoxy group, which is derivedfrom the preceding group and has the formula: ##STR4## a phenoxy group,a substituted phenoxy group (particularly a p-chlorophenoxy group), a3-pyridyl-methyleneoxy group, a5-(2-methyl-3-hydroxy-4-hydroxymethylpyridyl)-methyleneoxy group, whichhas the formula: ##STR5## a NZ₁ Z₂, NHCH₂ CH₂ NZ₁ Z₂, OCH₂ CH₂ NZ₁ Z₂ orO(CH₂)mCONZ₁ Z₂ group (where m is an integer from 1 to 4 and Z₁ and Z₂are C₁₋₄ alkyl groups, and Z₁ and Z₂ together with the nitrogen atom towhich they are joined may form a 5- to 7-membered N-heterocyclic groupwhich may contain a second heteroatom such as O and N and may besubstituted), or a group ##STR6## R' represents hydrogen, a C₁₋₄ alkylgroup or an acetyl group; and their addition salts.

Examples of the metal represented by M are Na, K, 1/2Ca, 1/2Mg, 1/2Zn,and 1/3Al, preferably Na or K.

The alkyl, alkoxy and alkylthio groups in the compounds according to theinvention contain a straight-chain or branched hydrocarbon radical.Among the C₁₋₄ alkyl groups, the methyl group is preferred for X₁, X₂,X₃, X₄, X₅, R and R' is methyl, while hydrogen, methyl, ethyl, isopropyland n-butyl are preferred for Z₁ and Z₂.

The C₁₋₁₂ alkoxy groups include the following preferred groups: methoxy,ethoxy, isopropyloxy, isobutyloxy, tert.butyloxy, 1-octyloxy,1-dodecyloxy, 2-pentyloxy and 3-pentyloxy.

The C₃₋₈ cycloalkyloxy groups preferred are the cyclopentyloxy,cyclohexyloxy and cyclooctyloxy groups.

Of the 5- to 7-membered N-heterocyclic NZ₁ Z₂ groups, which areoptionally substituted, the pyrrolidino, morpholino, piperidino,4-methylpiperidino, 4-methylpiperazino, 4-phenylpiperazino,4-p-chlorophenyl-piperazino and hexamethyleneimino groups areparticularly intended.

Of the Y-groups containing at least one nitrogen atom, the preferredgroups for Y=NZ₁ Z₂ are the N(CH₃)₂, N(C₂ H₅)₂, N(n-C₄ H₉), piperidinoand morpholino groups; the preferred groups for Y=NHCH₂ CH₂ NZ₁ Z₂ arethe 2-dimethylamino-ethylamino and 2-diethylamino-ethylamino groups; thepreferred groups for Y=OCH₂ CH₂ NZ₁ Z₂ are the hexamethyleneiminoethoxy,morpholinoethoxy, piperidinoethoxy and 2-diethylaminoethoxy groups.

By the term addition salts are understood the ammonium salts andacid-addition salts obtained with the compounds of formulae I and IIwhich have at least one amino group. The acid addition salts may beprepared by reacting the base with a mineral or organic acid,particularly with hydrochloric, fumaric, maleic and oxalic acids.

Various methods for synthesising the compounds I and II and theirintermediates are given hereinafter. These methods which relate tocompounds where A=substituted phenyl can of course be directlytransferred to compounds where A=heteroaryl.

The products prepared in accordance with these methods are given inTables I, II and III hereinafter. Some of the hydroxyketone intermediatecompounds formed in the synthesis of compounds in accordance with thepresent invention have been set out in Table IV.

In accordance with the invention there are provided therapeuticallyuseful compositions, particularly for the treatment of hyperlipaemia andcontaining as active ingredient a pharmaceutically active quantity of atleast one compound of formula I or II or a non-toxic acid addition saltthereof, in association with a physiologically acceptable excipient.

The compounds of formula II are obtained:

(1) From compounds of formula I according to the reaction scheme I asfollows: ##STR7##

The following comments may be made concerning this reaction scheme:

(a) the step I→IIa is preferentially effected using potassiumborohydride, but it is also possible to use a metal isopropylate.

(b) if A is ##STR8## and (i) X₁, X₂ or X₃ =NO₂, the reducing medium(step I→IIa) affects this NO₂ group; this type of compound shouldtherefore be prepared by a method which produces an alcohol group in anon-reducing medium (corresponds to item 2 under preparation of(4'-chlorophenyl)-(2-phenoxy-2-methylpropionic acid) carbinol). (ii) X₁,X₂ or X₃ =OH or NH₂, the compounds II in which R'=alkyl and acetyl areobtained indirectly; the OH or NH₂ group should in fact be introducedlast of all via a NO₂ group: the step NO₂ →OH is effected by a processknown per se; the step NO₂ →NH₂ is effected by catalytic reduction.

EXAMPLE Preparation of (4'-chlorophenyl)-(2-phenoxy-2-methylpropionicacid isopropyl ester) carbinol (alternative name isopropyl2-[4-(p-chloro-α-hydroxybenzyl)-phenoxy]-2-methyl propionate) ##STR9##

350 g of isopropyl 2-[4-(p-chlorobenzoyl)-phenoxy]-2-methylpropionate isdissolved in 4200 cm^(') of methanol in an Erlenmeyer flask, 60 g ofKBH₄ is added and the mixture is stirred for 8 hours at ambienttemperature; the methanol is then evaporated and the residue is taken upin water and methylene chloride; the organic phase is washed with wateruntil neutral and then dried, and the methylene chloride is evaporatedin vacuo; the remaining very clear oily residue is almost always verypure and may be used for any purpose; the yield is quantitative; (if asmall amount of the initial ketone remains this can easily be removedsimply by treating if with Girard's T reagent). N_(D) ²⁰ =1.5428

Preparation of (4'-chlorophenyl)-(2-phenoxy-2-methylpropionic acid)carbinol

A conventional hydrolysis in 4 N NaOH for 6 hours at 80°-85° C. givesthe expected acid-alcohol:

Yield: 95%

m.p.=132° C.

(2) Directly without proceeding via a ketone

In this process one of the techniques for obtaining compounds ofstructure I is used--see section Ab3 hereinafter; this is the methodwhich is especially preferred to obtain compounds II where X₁, X₂ or X₃=NO₂.

(3) According to a special process, shown in reaction scheme II asfollows. ##STR10##

All the stages in reaction scheme II are conventional. However, thisparticular reaction mechanism is unsuitable for synthesising alcoholsIIa where X₁, X₂ or X₃ =NH₂, OH, CF₃ or alkoxy.

The methods dealing with the synthesis of compounds of formula I aresummarised hereinafter.

A--DIRECT ACCESS TO COMPOUNDS OF FORMULA I

a--Methods employing a Friedel-Crafts reaction

Method Aa1: ##STR11##

The two industrial or known reactants III and IV are reacted in asolvent which is particularly suitable for carrying out a Friedel-Craftsreaction (carbon disulphide, dichloroethane, benzene, methylenechloride, nitrobenzene, nitromethane, compound IV itself). The catalystis a Lewis acid selected from aluminum chloride, tin tetrachloride,titanium tetrachloride, boron trifluoride and antimony pentafluoride.This latter compound (SbF₅) must definitely be used to carry out thereaction when one of the substituents X₁, X₂ or X₃ is the radical CF₃.

If one of the substituents X₁, X₂ or X₃ is NH₂ or OH, this method maynot be used directly, and it is necessary either to protect these groupsvia acetyl in the form ##STR12## or carry out the Friedel-Craftsreaction on a compound III bearing a group which will readily produceNH₂ and OH, for example a NO₂ group. Since the step NO₂ →NH₂ is aconventional reduction, the step NO₂ →OH may be carried out directly inaccordance with a process known per se.

As regards the substituents Y in compound IV which enable this type ofreaction to be carried out, the preferred are OCH₃ and OC₂ H₅, while theOH group should be excluded.

METHOD Aa2 ##STR13##

All the comments in the preceding paragraph apply equally in this caseand should be observed in exactly the same manner when performing thisreaction scheme, which relates solely to compounds in which A is aryl orheteroaryl.

As regards the compound ##STR14## this is obtained in a conventionalmanner according to one of the following reaction pathways:

b--Processes employing an organo-magnesium compound

These processes in fact utilise the property of organo-magnesiumcompounds by which they give ketones when reacted with a nitrile or acidchloride: ketones I will thus be obtained; if the same organo-magnesiumcompound is reacted not with a nitrile or acid chloride but with analdehyde, an alcohol of formula II is directly obtained.

METHOD Ab1

use of a nitrile ##STR15##

The condensation is carried out at a temperature between -10° C. and+30° C. in the solvent which was used to prepare the organo-magnesiumcompound VI (ether or THF). This organo-magnesium compound VI may in allcases be prepared from ##STR16## after salifying the acid group withNaOH(Y=ONa)or, better, by CH₃ MgI or C₂ H₅ MgBr (Y=OMgI, OMgBrrespectively).

The preparation of the organo-magnesium compound properly speaking:Br→MgBr, is effected by reacting the bromine derivative thus protectedwith magnesium, in ether or anhydrous THF. However, it is preferable tocarry out the two operations in one to prepare the "dimagnesium"compound VIa by exchange with CH₃ MgI. ##STR17##

Example illustrating this method Preparation of2-[(para-benzyl)-phenoxy]-2-methyl-propionic acid

26 g (0.1 mole) of 2-[(para-bromo)-phenoxy]-2-methyl-propionic acid isdissolved in 200 cc of anhydrous THF and placed in a 500 cc flask. Themixture is cooled in an ice bath and 0.2 mole of methylmagnesium iodide(prepared in solution of THF) is added slowly. After this addition, thetemperature is allowed to rise and the mixture stirred at ambienttemperature for 11/2 hours. Then slowly and drop by drop a solution of4.1 g (0.1 mole) of benzonitrile in 20 cc of THF is added and themixture is stirred for 2 hours 30 minutes at ambient temperature. Thereaction mixture is poured on to 500 cc of 10% hydrochloric acid, cooledby 500 g of ice, and vigorously stirred. The reaction mixture isextracted with ether and the ethereal phases are washed, dried anddecolorised. The ether solvent is evaporated under vacuum and the oilyresidue placed in a desiccator under vacuum.2-[(para-benzoyl)-phenoxy]-2-methylpropionic acid slowly crystallises(22 g). The yield is 77% and the melting point 130° C.

Method Ab2

Use of an acid chloride ##STR18##

In this case the condensation is carried out at a lower temperature(between -30° C. and +10° C.), care being taken to see that the acidchloride is never in excess (it is the acid chloride which will be addedto the organo-magnesium compound).

On the other hand, the use of a copper halide (CuBr, CuCl, CuI) which isreacted with VI (mole per mole) before adding the acid chloride veryoften gives better yields. The preparation of VI is carried out asmentioned above.

Non-limiting Example Preparation of2-[(para-4'-fluorobenzoyl)-phenoxy]-2-methyl-propionic acid

0.1 mole of dimagnesium halide of formula ##STR19## is prepared in a 500cc flask by the method described above. The reaction mixture is cooledto -25° C. and 19 g (0.1 mole) of cuprous iodide is added. A solution of10.7 g (0.1 mole) of p-fluorobenzoyl chloride in 50 cc of THF is addeddrop by drop over half-an-hour through a dropping funnel. Thetemperature is then allowed to rise to 15° to 20° C. and the mixturepoured on to 500 cc of 10% of HCl and 500 g of ice. After extractionwith ether, and washing, drying and decolorisation of the etherealphases, the solvent is evaporated under vacuum to give a solid residueof the desired acid. Yield 20 g (68%), melting point 160° C.

Method Ab3

Use of an aldehyde ##STR20##

The condensation is carried out at a temperature between -10° C. and+30° C., in the solvent which was used in the preparation of theorgano-magnesium compound VI (ether of THF). As regards VI compounds, itis obtained as described above.

Non-limiting Example Preparation of2-[p-(α-para-nitrobenzyl-α-hydroxy)-methyl]-phenoxy-2-methyl propionicacid ##STR21##

0.1 mole of the dimagnesium halide is prepared in a 500 cc flask asdescribed above. The reaction mixture is cooled in an ice bath and atthat temperature a solution of 15 g (0.1 mole) of p-nitrobenzaldehyde in30 cc of THF is added slowly. The mixture is allowed to return toambient temperature over a period of 2 hours whereupon it is hydrolysedand treated as described above. The desired acid alcohol produced is asolid melting at 148° C. Yield 71 g (64%).

These methods Ab1, Ab2 or Ab3 do not ensure direct access to compounds Ior II when A is ##STR22## where X₁, X₂ or X₃ are incompatible with areaction involving organo-magnesium compounds. This is also the casewhere X₁, X₂ or X₃ =NH₂ and OH; in this case the compounds of formula Iand II are obtained via X₁, X₂ or X₃ =NO₂ as described in Aa1.

c-processes using a phenol

Direct access to the isobutyric acid group

There are three possibilities, which are summarised in the followingreaction scheme: ##STR23##

Method Ac1 employing "acetone-chloroform" is preferred when R=CH₃, sinceit gives good yields; A slight modification to the method may be made,by isolating as an intermediate the acetone+chloroform reaction product,namely ##STR24## and reacting this compound with the hydroxyketone VIIin alkaline medium.

EXAMPLE Preparation of 2-(4-(p-chlorobenzoyl)-phenoxy)-2-methylpropionicacid

12 l of anhydrous acetone, 1.395 kg (6 moles) of4-chloro-4-hydroxybenzophenone and 1.44 kg (6 moles) of soda are placedin a 20-liter flask; the reaction mixture is heated 1 to 2 hours underreflux to form the phenate, the source of heat is removed, and a mixtureof 2.16 kg of chloroform (18 moles) diluted in 3.5 liters of acetone isthen added.

The addition of the mixture is sufficient to maintain reflux for atleast 6 hours; after 4 hours (when one-quarter of the mixture remains tobe added) the exothermicity of the reaction decreases, and heating isrecommenced to maintain the reflux for 6 to 8 hours after the end of theaddition; the mixture is allowed to cool and the sodium chloride whichhas precipitated is filtered off (the sodium salt of the desired acid isdissolved in the acetone); the acetone is evaporated in vacuo and theresidue is dissolved in the minimum amount of lukewarm water(approximately 35° C.); this aqueous phase is washed very carefully withdichloroethane (3-4 times) and is then acidified to a pH-value of 1 byHCl while cooling, whereupon the acid precipitates; the reaction mixtureis shaken vigorously, and after 30 minutes this acid is suction-dried,washed with copious amounts of water and then dried.

Weight=1.61 kg;

m.p.=182° C.;

Yield: 85%

This acid contains a few traces (3 to 4%) of unreacted phenol, but sinceall the other impurities have been able to be eliminated by means ofthis simple treatment it would be quite pointless to carry outpurification of this acid with sodium bicarbonate (this is industriallyvery beneficial).

To obtain the acid pure as such, it is recrystallised in toluene;m.p.=185° C.

Method Ac2 employing ##STR25## (the bromine may be replaced by Cl or I)is particularly preferred when R=H or when one of the substituents X₁,X₂ or X₃ of the group A is NO₂ or CF₃. This condensation is carried outin ethyl alcohol or isobutyl methyl ketone in the presence of K₂ CO₃.

Non-limiting Example Preparation of Ethyl2-[4-(para-chlorobenzoyl)-phenoxy]-propionate

0.75 mole (175 g) of 4'-chloro-4-hydroxy-benzophenone, 1.5 l ofmethylisobutylketone, 0.975 mole (134 g) of K₂ CO₃ and 0.8 mole (145 g)of ethyl 2-bromopropionate are placed in a 2-liter flask. The mixture isheated at reflux for 8 hours with vigorous agitation whereupon thereaction mixture is cooled and filtered on a Buchner funnel. The solventis then evaporated under vacuum and the residue distilled; the desiredester is recovered at 198° to 201° C. under 0.1 mm of mercury. Yield 190g (76%).

The reaction (method Ac3) using 2-hydroxy-isobutyric acid, involves adehydration which can be carried out in solution of DMF or tolueneeither (i) in an acid medium (H₂ SO₄, paratoluene-sulphonic acid) or(ii) in an alkaline medium, with mechanism (i) being preferred. Thismethod is derived from the description of German Patent Application DOSNo. P 2112 272 5.

In the preferred method, which uses acetone-chloroform, the followingacid is obtained as an intermediate compound: ##STR26## This is thenconverted to an amide or ester as the case may be.

The conversion of the acids of formula I into amides and esters is givenbelow in a general manner:

Conversion into amide or ester (tertiary alcohol, alcohol amide or3-pyridylmethanol).

First the acid chloride is synthetised from the acid and phosphoruspentachloride until cold (0°-5° C.). The acid chloride is reacted withthe amine or alcohol desired in the presence of a tertiary amine(triethylamine or pyridine) to neutralise the hydrochloric acid formed.

Non-limiting Example

Preparation of the amido-ester of formula ##STR27##

32 g (0.1 mole) of 2[4-(p-chlorobenzoyl)-phenoxy]-2-methylpropionic acidis suspended in 250 cc of dry toluene, and cooled in an ice bath. 20 gof phosphorous pentachloride is then added little by little. Thereaction mixture is stirred for 2 hours at this temperature and wheneverything has dissolved, the toluene and the phosphorus oxychlorideformed are evaporated off. The solid residue, which has a melting pointof 80° C., is recrystallised from hexane: it is the acid chloride. Topurify this crude material, it is re-dissolved in the minimum quantityof toluene and 0.1 mole of pyridine (8 g) and, slowly, 0.1 mole (13 g)of 4-hydroxy-N,N-dimethyl-butyramide is added. The reaction is completedby heating for 1 hour on a water bath at 50° C. Then the mixture isallowed to cool and the pyridinium hydrochloride filtered off. Thefiltered organic phase is washed with water, dried and decolorised andthe solvent is evaporated off under vacuum. The desired estercrystallises. Yield 35 g (22%). Melting point 92° C.

Conversion into ester (using a secondary or primary alcohol)

Direct esterification is carried out, the esterification process beingone which has particularly been investigated and adapted for use with asecondary alcohol. Accordingly, this original process can be used in thecase of a primary alcohol with reaction kinetics which are definitelyfaster; this method consists in carrying out esterification with arelatively small amount of the chosen alcohol (1 to 1.5 liters ofalcohol per 1 kg of acid of formula I and 0.6 kg of sulphuric acid per 1kg of acid of formula I).

EXAMPLE Preparation of 2-(4-(p-chlorobenzoyl)-phenoxy)-2-methylpropionicacid isopropyl ester

1 kg of the preceding acid is suspended in 1.5 l of isopropanol; 600 gof sulphuric acid is slowly added and the reaction mixture is refluxedfor 12 hours. The mixture is allowed to cool, the ester crystallises, iscarefully suction dried, is washed with 1% concentration soda whileshaking, is suction dried again, and is recrystallised in 1.5 l ofisopropanol in the presence of animal charcoal; the product whichrecrystallises is pure:

Weight=1.020 kg;

m.p.=80° C.;

Yield: 85%

Transformation into ester (with an amino alcohol or alcohol amide)

The reaction may of course be carried out with the acid chloride, butthe preferred method is a transesterification starting from a simpleester (methyl ester for example) and the chosen aminoalcohol or alcoholamide. The catalyst may be sodium, a metal isopropylate (titaniumisopropylate being preferred) or APTS.

Non-limiting Example Preparation of Diethylaminoethyl2-(p-benzoylphenoxy)-2-methylpropionate ##STR28##

299 g (1 mole) of methyl 2-(p-benzoylphenoxy)-2-methylpropionate, 30 gof titanium isopropylate and 117 g (1 mole) of diethylaminoethanol areplaced in a 500-cc flask. The reaction mixture is heated for 45 minutesat 120° C. (interior temperature) so as to distil off all the alcoholformed. The mixture is then allowed to cool and poured on to 10%hydrochloric acid in the presence of ether. The aqueous phase is madealkaline and then extracted with methylene chloride. The organic phaseis carefully washed with water, then dried, decolorised and concentratedunder vacuum. The residual oil is the desired ester. Yield 264 g, 69%.The maleate salt melts at 62° C.

For the preparation of hydroxyketones VII ##STR29## the common startingmaterial for all the products prepared by the methods Ac contemplatedare those obtained by one of the following two methods:

The first reaction scheme is carried out regardless of the A group##STR30## In the second method the reaction is carried out wherein A isthe group ##STR31##

A similar technique has also been contemplated concerning the first stepparagraph Aa. The second demethylation stage is conducted with 48% HBror aluminium chloride of pyridinium hydrochloride.

Non-limiting Example Preparation of 4'-chloro-4-hydroxybenzophenone

510 g of aluminium chloride (3.82 M), then 3.5 l of dry methylenechloride, and, slowly, 430 g (4 M) of anisole are added to a 5-literflask; the flask is cooled to maintain the temperature at about 25° C.,and 600 g (3.44 M) of 4-chlorobenzoyl chloride is then added dropwise;the reaction mixture is next heated 6 hours under reflux, is left tocool to about 25° C., and the reaction mixture is poured onto 5 kg ofice and 0.5 l of concentrated HCl; the mixture is stirred well duringthis hydrolysis; the methylene chloride phase is decanted, washed oncewith water, and transferred to another 5-liter vessel. The methylenechloride is removed by evaporation and replaced in the flask by 2 l ofchlorobenzene; a Dean-Stark apparatus is connected and the reactionmixture is refluxed to dehydrate the medium; when this operation iscomplete the mixture is cooled to approximately 50° C. and 800 g (6 M)of aluminium chloride is added; the reaction mixture is heated 1 hour 30minutes under reflux (very gentle reflux), and demethylation proceedsrapidly; the reaction mixture is cooled and poured onto 6 kg of ice and0.5 l of concentrated HCl; the mixture is stirred for 1 hour 30 minutesand the precipitate is dried; the latter is washed with water, withmethylene chloride, and then dried:

Weight=720 g;

m.p.=178° C.;

Yield: 90%

β-Methods using an organometallic compound

It is possible to use the methods previously described in paragraph Abor in paragraph Ba1 below (organolithium compounds). The followingreaction scheme and non-limiting example are given to illustrate thismethod. ##STR32##

Non-limiting Example Preparation of3'-trifluoromethyl-4-hydroxybenzophenone

0.15 mole (90 cc) of n-butyl lithium is cooled to -70° C. in ether. 34 g(0.1 mole) of 3-trifluoromethyl-bromobenzene is added drop by drop. Themixture is stirred for 5 minutes at -70° C. after the addition and,still at that temperature 23 g (0.15 mole) of sodium4-methoxyphenylcarboxylate is added. The temperature is allowed to riseto the ambient and the mixture is then stirred for 16 hours at ambienttemperature. The mixture is hydrolysed and extracted with ether and theethereal phase is washed with water, dried, decolorised, andconcentrated. There remains an oil which crystallises from hexane. Yield32 g (76%). Melting point 65° C.

To carry out demethylation, the 32 g of the oil obtained in the precedinparagraph is refluxed for 30 minutes with 170 g of pyridiniumhydrochloride. The mixture is allowed to cool, taken up in 10%hydrochloric acid and extracted with ether and the ethereal phase isextracted with 2 N soda than acidified with HCl. The product isprecipitated. Yield 28 g. Melting Point 129° C.

γ--Method using a bromine derivative ##STR33## Non-limiting ExamplePreparation of 4-(α-thenoyl)-phenol ##STR34##

A mixture of 20 g of 4-(α-thenoyl)-bromobenzene, 4 g of anhydrous cupricoxide and 10 g of sodium methoxide in 130 cc of anhydrous methanol isrefluxed for 20 hours in a 250 cc flask. Subsequently the mixture isfiltered and the methanol evaporated off, resulting in a yield of 15.3 gof 4-(α-thenoyl)-anisole. (Melting point 73° C.). This is demethylatedwith aluminium chloride in chlorobenzene as described above and 13 g ofthe desired phenol is obtained. Yield 85%. Melting point 86° C.

δ--Particular Instance

Production of ##STR35## where at least 2 substituents are methoxy.

In the first stage the ether chosen need not be a methyl ether and at-butyl of the formula ##STR36## is synthesised by one of the threepreceding methods α, β or γ from which the hydroxyketone VIImethoxylated at X₁, X₂ or X₃ can easily be regenerated (by APTS forexample).

ε Methods not involving the intermediate ether

The OH residue of VII is introduced (1) directly by ##STR37## Thismethod gives excellent yields when A is alkyl.

(2) by an intermediate sulphonic acid ##STR38##

(3) by an intermediate nitro compound ##STR39## This last method isgenerally interesting and on the other hand of particular interest forpreparing a final product of formula I having a hydroxy substituent (forexample X₁, X₂ or X₃ in radical A). This method has been used severaltimes and it is illustrated below by two examples.

Non-limiting Example Preparation of 4'-chloro-4-hydroxybenzophenone

250 cc of DMSO and 4.8 g sodium hydride are placed in a 500 cc flask andheated at 70° C. for 1 hour, by which time the solution has becomeclear. A solution of 24.2 g (0.2 mole) of benzaldoxime in 100 cc of DMSOis then added drop by drop. The solution is maintained at 70° C. for 1hour, then allowed to cool to 15° C. A solution of 26 g (0.1 mole) of4'-chloro-4-nitrobenzophenone in 150 cc of DMSO is then added. Thereaction mixture is stirred for 20 hours at ambient temperature and thenpoured into acidulated water. The mixture is extracted with ether andthen with ether containing 2 N caustic soda. On acidification theproduct is precipitated. Yield 15 g (65%). Melting point 178° C.

Non-limiting Example Preparation of Isopropyl2-[4-(4-hydroxybenzoyl)-phenoxy]-2-methylpropionate ##STR40##

The mode of operation is identical with the above; however, to avoid thesaponification of the ester function of the starting material, which hasthe formula ##STR41##

the latter is dissolved in DMSO at 8° C. and the sodium salt ofbenzaldoxime suspended in DMSO, (first stage in the preparation) isadded little by little with a spatula. The treatment is identical withthat indicated in the preceding example and the desired product isobtained in a yield of 76%, melting point 124° C.

In Table IV below all the hydroxyketones used, and their mode ofoperation are set out: it is also indicated which of them are novelcompounds.

B--Access to compounds of formula I via products having a potentialcarboxylic acid group

The potential carboxylic acid group chosen is an "isobutyric" aldehydewhich is protected as an acetal: ##STR42## where Y is C₁₋₄ alkyl,preferably C₂ H₅, so that the following processes (a) and (b) can beemployed:

(a) Processes employing an organo-metallic compound

The property which organo-metallic compounds have, depending on theirnature, of forming ketones when they are reacted with a nitrile, an acidchloride or a carboxylic acid salt, is utilised: ketones of the formula:##STR43## are thus obtained as intermediates. The aldehyde isregenerated by hydrolysis of the acetal VIII and is oxidised to theacid, the acid then being subjected to esterification or amidationreactions.

METHOD Pa1

Use of an organo-lithium compound

The reaction mechanisms are summarized hereinafter (with Y₃ and C₂ H₅)##STR44##

The compound IX is lithiated with Bu-Li in ether at a temperaturebetween -70° C. and 0° C., and the product thus obtained is reacted withthe sodium salt of the acid ACOOH (or the corresponding nitrile) atambient temperature; the ketone X thus obtained is treated in an acidmedium and liberates a ketone-aldehyde which is oxidised with potassiumpermanganate, the acid obtained being esterified or amidated inaccordance with the processes described previously. The compounds IX arenovel and are obtained conventionally in accordance with the followingreaction scheme: ##STR45## As has already been stated above (at Ab3),compound X in which A is ##STR46## and X₁, X₂ or X₃ =NH₂ or OH cannot beobtained directly by this method; such compounds are obtained from thecorresponding nitro derivative (X₁, X₂ or X₃ =NO₂).

METHOD Ba2

Use of an organo-magnesium compound ##STR47## The organo-magnesiumcompound may be obtained from IX either directly (Mg in ether or THF),or by exchange with CH₃ MgI. Condensation of this organo-magnesiumcompound with an acid chloride or a nitrile is subject to the samecomments as those expressed at Ab. Of course, the compounds where X orX₁, X₂ or X₃ =OH or NH₂ can only be obtained from a corresponding nitroderivative.

(b) Processes employing a "hydroxyketone"

This simply involves condensing a hydroxyketone with a brominated acetalin alkaline medium according to the reaction ##STR48## the procedurebeing as described for ##STR49## at Ac, the condensation product X thusobtained being treated as mentioned above to give the compound I.

Non-limiting Example Method for preparing compounds of formula I inwhich X₀ is --O(CH₂)₂ --O--(1,3-dioxolane derivatives)

These compounds are obtained by the action of ethyleneglycol in thepresence of APTS on compounds of formula I in which X₀ is oxygen and Yis other than hydrogen; the 1,3-dioxolane derivatives are obtained. Theycannot be converted to the corresponding acids (Y=OH) by saponification.It is necessary in fact to stop at the alkali salt (X₀ =--O(CH₂)₂ O--because acid cleaves the dioxolane previously formed and regenerates theketone acid.

                                      TABLE I                                     __________________________________________________________________________     ##STR50##                                                                                                                            Melting                                                                       point                                                                         (°C.)                                                                  or other                                                                      physical              Pro-                                                                             Code                                                 characteristic        duct                                                                             No.                                                                                A         X.sub.4                                                                           X.sub.5                                                                           R      Y                      if                    __________________________________________________________________________                                                            indicated             A-1                                                                               88                                                                               ##STR51##  H   H   CH.sub.3                                                                          OH                        130                   A-2                                                                              153                                                                               ##STR52##  H   H   CH.sub.3                                                                          OH                        185                   A-3                                                                              162                                                                               ##STR53##  H   H   CH.sub.3                                                                          OCH.sub. 3                 89                   A-4                                                                              163                                                                               ##STR54##  H   H   CH.sub.3                                                                          OC.sub.2 H.sub.5           79                   A-5                                                                              170                                                                               ##STR55##  H   H   CH.sub.3                                                                           ##STR56##                160                   A-6                                                                              171                                                                               ##STR57##  H   H   CH.sub.3                                                                           ##STR58##                148                   A-7                                                                              178                                                                               ##STR59##  H   H   CH.sub.3                                                                           ##STR60##                 80                   A-8                                                                              180                                                                               ##STR61##  H   H   CH.sub.3                                                                          OCH.sub.3                  58                   A-9                                                                              186                                                                               ##STR62##  H   H   CH.sub.3                                                                          OC.sub.2 H.sub.5           87                   A-10                                                                             190                                                                               ##STR63##  H   H   CH.sub.3                                                                           ##STR64##                 84                   A-11                                                                             208                                                                               ##STR65##  H   H   CH.sub.3                                                                           ##STR66##                100                   A-12                                                                             209                                                                               ##STR67##  H   H   CH.sub.3                                                                           ##STR68##                118                   A-13                                                                             211                                                                               ##STR69##  H   H   CH.sub.3                                                                           ##STR70##                115                   A-14                                                                             212                                                                               ##STR71##  H   H   CH.sub.3                                                                           ##STR72##                 62                   A-15                                                                             217                                                                               ##STR73##  H   H   CH.sub.3                                                                           ##STR74##                135                   A-16                                                                             229                                                                               ##STR75##  H   H   CH.sub.3                                                                           ##STR76##                122                   A-17                                                                             230                                                                               ##STR77##  H   H   CH.sub.3                                                                           ##STR78##                104                   A-18                                                                             231                                                                               ##STR79##  H   H   CH.sub.3                                                                           ##STR80##                116                   A-19                                                                             238                                                                               ##STR81##  H   H   CH.sub.3                                                                           ##STR82##                144                   A-20                                                                             239                                                                               ##STR83##  H   H   CH.sub.3                                                                           ##STR84##                145                   A-21                                                                             253                                                                               ##STR85##  3'-CH.sub.3                                                                       H   CH.sub.3                                                                           ##STR86##                Boiling point                                                                 220° C./                                                               0.01 mm Hg            A-22                                                                             259                                                                               ##STR87##  H   H   CH.sub.3                                                                           ##STR88##                oil                   A-23                                                                             328                                                                               ##STR89##  H   H   CH.sub.3                                                                           ##STR90##                176                   A-24                                                                             340                                                                               ##STR91##  H   H   CH.sub.3                                                                           ##STR92##                125                   A-25                                                                             384                                                                               ##STR93##  H   H   CH.sub.3                                                                           ##STR94##                 90                   A-26                                                                             385                                                                               ##STR95##  H   H   CH.sub.3                                                                          OC.sub.12 H.sub.25         47                   A-27                                                                             386                                                                               ##STR96##  H   H   CH.sub.3                                                                          SEt                        49                   A-28                                                                             387                                                                               ##STR97##  H   H   CH.sub.3                                                                           ##STR98##                117                   A-29                                                                             388                                                                               ##STR99##  H   H   CH.sub.3                                                                          OC.sub.8 H.sub.17         n .sub.20.sup.D =                                                             1.535                 A-30                                                                             401                                                                               ##STR100## H   H   CH.sub.3                                                                          OH                        196                   A-31                                                                             402                                                                               ##STR101## H   H   CH.sub.3                                                                           ##STR102##               115                   A-32                                                                             403                                                                               ##STR103## H   H   CH.sub.3                                                                           ##STR104##                79                   A-33                                                                             404                                                                               ##STR105## H   H   CH.sub.3                                                                          OH                        155                   A-34                                                                             405                                                                               ##STR106## H   H   CH.sub.3                                                                           ##STR107##                69                   A-35                                                                             406                                                                               ##STR108## H   H   CH.sub.3                                                                          OH                        121                   A-36                                                                             507                                                                               ##STR109## H   H   CH.sub.3                                                                          OH                        182                   A-37                                                                             512                                                                               ##STR110## 3'-CH.sub.3                                                                       5'-CH.sub.3                                                                       CH.sub.3                                                                           ##STR111##                67                   A-38                                                                             517                                                                               ##STR112## 3'-CH.sub.3                                                                       5'-CH.sub.3                                                                       CH.sub.3                                                                          OH                         92                   A-39                                                                             518                                                                               ##STR113## H   H   CH.sub.3                                                                           ##STR114##                98                   A-40                                                                             573                                                                               ##STR115## H   H   CH.sub.3                                                                          OH                        144                   A-41                                                                             573A                                                                              ##STR116## H   H   CH.sub.3                                                                           ##STR117##                95                   A-42                                                                             575                                                                               ##STR118## H   H   CH.sub.3                                                                           ##STR119##               130                   A-43                                                                             590                                                                               ##STR120## H   H   CH.sub.3                                                                          OH                        114                   A-44                                                                             602                                                                               ##STR121## H   H   CH.sub.3                                                                          OH                        129                   A-45                                                                             606                                                                               ##STR122## H   H   CH.sub.3                                                                          OH                        182                   A-46                                                                             606A                                                                              ##STR123## H   H   CH.sub.3                                                                           ##STR124##               120                   A-47                                                                             607                                                                               ##STR125## H   H   CH.sub.3                                                                          OH                        126                   A-48                                                                             611                                                                               ##STR126## H   H   CH.sub.3                                                                           ##STR127##               120                   A-49                                                                             618                                                                               ##STR128## H   H   CH.sub.3                                                                          OH                        158                   A-50                                                                             619                                                                               ##STR129## H   H   CH.sub.3                                                                          OH                        160                   A-51                                                                             627                                                                               ##STR130## H   H   CH.sub.3                                                                           ##STR131##               124                   A-52                                                                             634                                                                               ##STR132## H   H   CH.sub.3                                                                          OH                        192                   A-53                                                                             --                                                                                ##STR133## H   H   CH.sub.3                                                                           ##STR134##                68                   A-54                                                                             398                                                                               ##STR135## H   H   H   OH                        146                   A-55                                                                             399                                                                               ##STR136## H   H   H                                                                                  ##STR137##                97                   A-55 bis                                                                         624                                                                               ##STR138## 2'-CH.sub.3                                                                       6'-CH.sub.3                                                                       CH.sub.3                                                                          OH                        120                   A-56                                                                             632                                                                               ##STR139## H   H   CH.sub.3                                                                           ##STR140##                70                   A-57                                                                             643                                                                               ##STR141## H   H   CH.sub.3                                                                          OC(CH.sub.3 ).sub.3        77                   A-58                                                                             644                                                                               ##STR142## H   H   CH.sub.3                                                                           ##STR143##               176                   A-59                                                                             --                                                                                ##STR144## H   H   CH.sub.3                                                                           ##STR145##               n .sub.D.sup.20 =                                                             1.5535                A-60                                                                             645                                                                               ##STR146## H   H   CH.sub.3                                                                          O(CH.sub.2).sub.2 CON(CH.sub.3).sub.2                                                                    90                   A-61                                                                             642                                                                               ##STR147## H   H   CH.sub.3                                                                          OH                        108                   A-62                                                                             641                                                                               ##STR148## H   H   CH.sub.3                                                                          OCH(CH.sub.3).sub.2       n .sub.D.sup.20 =                                                             1.516                 A-63                                                                             --                                                                                ##STR149## H   H   CH.sub.3                                                                          OH                        129                   A-64                                                                             --                                                                                ##STR150## H   H   CH.sub.3                                                                          OCH(CH.sub.3).sub.2        38                   A-65                                                                             --                                                                                ##STR151## H   H   CH.sub.3                                                                          OH                        --                    A-66                                                                             --                                                                                ##STR152## H   H   CH.sub.3                                                                          OCH(CH.sub.3).sub.2       --                    A-67                                                                             635                                                                               ##STR153## H   H   CH.sub.3                                                                          OCH(CH.sub.3).sub.2        85                   A-68                                                                             559                                                                              (CH.sub.3).sub.2CH                                                                        H   H   CH.sub.3                                                                          OH                        --                    A-69                                                                             538                                                                              (CH.sub.3).sub.2CH                                                                        H   H   CH.sub.3                                                                          OCH(CH.sub.3).sub.2       --                    A-70                                                                             637                                                                               ##STR154## H   H   CH.sub.3                                                                           ##STR155##                64                   A-71                                                                             639                                                                               ##STR156## H   H   CH.sub.3                                                                           ##STR157##                92                   A-72                                                                             --                                                                                ##STR158## H   H   CH.sub.3                                                                          OCH(CH.sub.3)CH.sub.2 CH.sub.2 CH.sub.3                                                                  55                   A-73                                                                             --                                                                                ##STR159## H   H   CH.sub.3                                                                          OCH(C.sub.2 H.sub.5).sub.2                                                                               67                   A-74                                                                             --                                                                                ##STR160## H   H   CH.sub.3                                                                          OCH(CH.sub.3)CH.sub.2 CH.sub.3                                                                           82                   A-75                                                                             --                                                                                ##STR161## H   H   CH.sub.3                                                                          OC.sub.8 H.sub.17          38                   A-76                                                                             --                                                                                ##STR162## H   H   CH.sub.3                                                                           ##STR163##               114                   A-77                                                                             --                                                                                ##STR164## H   H   CH.sub.3                                                                           ##STR165##               138                   A-78                                                                             --                                                                                ##STR166## H   H   CH.sub.3                                                                           ##STR167##               160                   A-79                                                                             --                                                                                ##STR168## H   H   CH.sub.3                                                                          OC.sub.12 H.sub.25         37                   A-80                                                                             --                                                                                ##STR169## H   H   CH.sub.3                                                                           ##STR170##               hygroscopic           A-81                                                                             --                                                                                ##STR171## H   H   CH.sub.3                                                                           ##STR172##               125                   A-82                                                                             272                                                                               ##STR173## H   H   H                                                                                  ##STR174##               110                   A-83                                                                             391                                                                              cyclohexyle H   H   CH.sub.3                                                                          OH                        148                   A-84                                                                             390                                                                              cyclohexyle H   H   CH.sub.3                                                                          OCH(CH.sub.3).sub.2        67                   A-85                                                                             -- 4-CH.sub.3 OC.sub.6 H.sub.4                                                               H   H   CH.sub.3                                                                          OC.sub.12 H.sub.25         38                   A-86                                                                             -- 4-CH.sub.3 OC.sub.6 H.sub.4                                                               H   H   CH.sub.3                                                                          OCH(CH.sub.3)C.sub.2 H.sub.5                                                                             74                   A-87                                                                             -- 4-ClC.sub.6 H.sub.4                                                                       2'-CH.sub. 3                                                                      6'-CH.sub. 3                                                                      CH.sub.3                                                                          O CH(CH.sub.3).sub.2       70                   __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________     ##STR175##                                                                   Product                                                                            X.sub.1                                                                            X.sub.2                                                                            X.sub.3                                                                            X.sub.4                                                                           X.sub.5                                                                           R  R'   Y                                         __________________________________________________________________________    B-1 (a)                                                                             4-Cl  H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-2 (b)                                                                             4-Cl  H    H    H   H   CH.sub.3                                                                         H    OH                                      B-3 (c)                                                                             4-Cl  H    H    H   H   CH.sub.3                                                                         H    OH                                      B-4 (d)                                                                             4-Cl  H    H    H   H   CH.sub.3                                                                         CH.sub.3                                                                           OCH(CH.sub.3).sub.2                     B-5   4-Cl  H    H    H   H   CH.sub.3                                                                         COCH.sub. 3                                                                        OCH(CH.sub.3).sub.2                     B-6   4-Cl  H    H    H   H   CH.sub.3                                                                         H    OCH.sub.3                               B-7   4-Cl  H    H    H   H   CH.sub.3                                                                         H    OC.sub.2 H.sub.5                        B-8   4-Cl  H    H    H   H   CH.sub.3                                                                         H                                                                                   ##STR176##                             B-9   4-Cl  H    H    H   H   CH.sub.3                                                                         H                                                                                   ##STR177##                             B-10  H     H    H    H   H   CH.sub.3                                                                         H    OH                                      B-11  H     H    H    H   H   CH.sub.3                                                                         H    OCH.sub.3                               B-12  H     H    H    H   H   CH.sub.3                                                                         H    OC.sub.2 H.sub.5                        B-13  H     H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-14  H     H    H    H   H   CH.sub.3                                                                         H                                                                                   ##STR178##                             B-15  H     H    H    H   H   CH.sub.3                                                                         H                                                                                   ##STR179##                             B-16  H     H    H    H   H   CH.sub.3                                                                         H                                                                                   ##STR180##                             B-17  H     H    H    H   H   CH.sub.3                                                                         H    O(CH.sub.2).sub.2N(C.sub.2 H.sub.5                                            ).sub.2, maleate                        B-18  4-Cl  H    H    H   H   CH.sub.3                                                                         H                                                                                   ##STR181##                             B-19  4-Cl  H    H    H   H   CH.sub.3                                                                         H                                                                                   ##STR182##                             B-20  4-Cl  H    H    H   H   CH.sub.3                                                                         H    O(CH.sub.2).sub.2 N(C.sub.2                                                   H.sub.5)2, HCl                          B-21  4-Cl  H    H    3'-CH.sub.3                                                                       H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-22  4-Cl  H    H    H   H   CH.sub.3                                                                         H    clyclooctyloxy                          B-23  4-Cl  H    H    H   H   CH.sub.3                                                                         H    O(CH.sub.2).sub.11 CH.sub.3             B-24  4-Cl  H    H    H   H   CH.sub.3                                                                         H    O(CH.sub.2).sub.7 CH.sub.3              B-25  2-Cl  6-Cl H    H   H   CH.sub.3                                                                         H    OH                                      B-26  2-Cl  6-Cl H    H   H   CH.sub.3                                                                         CH.sub.3                                                                           OH                                      B-27  2-Cl  6-Cl H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-28  2-Cl  6-Cl H    H   H   CH.sub.3                                                                         CH.sub.3                                                                           OCH(CH.sub.3).sub.2                     B-29  3-Cl  H    H    H   H   CH.sub.3                                                                         H    OH                                      B-30  3-Cl  H    H    H   H   CH.sub.3                                                                         CH.sub.3                                                                           OH                                      B-31  3-Cl  H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub. 3).sub.2                    B-32  3-Cl  4-Cl H    H   H   CH.sub.3                                                                         H    OH                                      B-33  3-Cl  4-Cl H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-34 (e)                                                                            4-Br  H    H    H   H   CH.sub.3                                                                         H    OH                                      B-35  4-Br  H    H    H   H   CH.sub.3                                                                         H    OH                                      B-36 (f)                                                                            4-Br  H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-37  4-Cl  H    H    3'-CH.sub.3                                                                       5'-CH.sub.3                                                                       CH.sub.3                                                                         H    OH                                      B-38  4-Cl  H    H    3'-CH.sub.3                                                                       5'-CH.sub.3                                                                       CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-39 (g)                                                                            4-OCH.sub.3                                                                         H    H    H   H   CH.sub.3                                                                         H    OH                                      B-40 (h)                                                                            4-OCH.sub.3                                                                         H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-41  2-Cl  H    H    H   H   CH.sub.3                                                                         H    OH                                      B-42  2-Cl  H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-43  2-CH.sub.3                                                                          H    H    H   H   CH.sub.3                                                                         H    OH                                      B-44  2-CH.sub.3                                                                          H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-45  4-NO.sub.2                                                                          H    H    H   H   CH.sub.3                                                                         H    OH                                      B-46  4-NO.sub.2                                                                          H    H    H   H   CH.sub.3                                                                         H    OH                                      B-47  2-CH.sub.3                                                                          6-CH.sub.3                                                                         H    H   H   CH.sub.3                                                                         H    OH                                      B-48  4-NH.sub.2                                                                          H    H    H   H   CH.sub.3                                                                         H    OH                                      B-49  4-NH.sub.2                                                                          H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-50  4-F   H    H    H   H   CH.sub.3                                                                         H    OH                                      B-51  4-F   H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-52  4-OH  H    H    H   H   CH.sub.3                                                                         H    OH                                      B-53  4-OH  H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-54  4-Cl  H    H    H   H   H  H    OH                                      B-55  4-Cl  H    H    H   H   H  H    OCH(CH.sub.3).sub.2                     B-56  4-Cl  H    H    H   H   CH.sub.3                                                                         H                                                                                   ##STR183##                             B-57  4-Cl  H    H    H   H   CH.sub.3                                                                         CH.sub.3                                                                            ##STR184##                             B-58  4-Cl  H    H    H   H   CH.sub.3                                                                         H    OC(CH.sub.3).sub.3                      B-59  4-Cl  H    H    H   H   CH.sub.3                                                                         H    OCH.sub.2 CHOHCH.sub.2 OH               B-60  4-Cl  H    H    H   H   CH.sub.3                                                                         H    O(CH.sub.2).sub.2 CON(CH.sub.3).sub.                                          2                                       B-61  3-CF.sub.3                                                                          H    H    H   H   CH.sub.3                                                                         H    OH                                      B-62  3-CF.sub.3                                                                          H    H    H   H   CH.sub.3                                                                         H    OCH(CH.sub. 3).sub.2                    B-63  3-OCH.sub.3                                                                         4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        H   H   CH.sub.3                                                                         H    OH                                      B-64  3-OCH.sub.3                                                                         4-OCH.sub.3                                                                        5-OCH.sub.3                                                                        H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     B-65  3-OCH.sub.3                                                                         4-Cl H    H   H   CH.sub.3                                                                         H    OH                                      B-66  3-OCH.sub.3                                                                         4-Cl H    H   H   CH.sub.3                                                                         H    OCH(CH.sub.3).sub.2                     __________________________________________________________________________     Notes:-                                                                       (a) : n.sub.D.sup.20  = 1.5428;                                               (b) : M.P. = 132° C.;                                                  (c) : M.P. = 99° C.;                                                   (d) : n.sub.D.sup.20  = 1.5532;                                               (e) M.P. = 122° C.;                                                    (f) : n.sub.D.sup.20  = 1.550;                                                (g) : M.P. = 120° C.;                                                  (h) : n.sub.D.sup.20  = 1.543.                                           

                                      TABLE III                                   __________________________________________________________________________     ##STR185##                                                                        Code                                   M.P.                              Product                                                                            No.                                                                              Z                     X.sub.4                                                                         X.sub.5                                                                         R     Y   (°C.)                      __________________________________________________________________________    C-1  --                                                                                ##STR186##           H H CH.sub.3                                                                         OK     --                                C-2  --                                                                                ##STR187##           H H CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                  --                                C-3  574                                                                               ##STR188##           H H CH.sub.3                                                                         OH     162                               C-4  --                                                                                ##STR189##           H H CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                   67                               C-5  --                                                                                ##STR190##           H H CH.sub.3                                                                         OH     --                                C-6  --                                                                                ##STR191##           H H CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                  --                                C-16 640                                                                               ##STR192##           H H CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                   72                               C-7  491                                                                               ##STR193##           H H CH.sub.3                                                                         OH     156                               C-8  493                                                                               ##STR194##           H H CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                   63                               C-9  515                                                                               ##STR195##           H H CH.sub.3                                                                         OH     131                               C-10 --                                                                                ##STR196##           H H CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                  --                                C-11 --                                                                                ##STR197##           H H CH.sub.3                                                                         OH     --                                C-12 541                                                                               ##STR198##           H H CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                   72                               C-13 612                                                                               ##STR199##           H H CH.sub.3                                                                         OH     132                               C-14 --                                                                                ##STR200##           H H CH.sub.3                                                                         OCH(CH.sub.3).sub.2                                                                  n .sub.D.sup.20  = 1,5455         C-15 --                                                                                ##STR201##           H H CH.sub.3                                                                         OH     185                               __________________________________________________________________________

                  TABLE IV                                                        ______________________________________                                         ##STR202##                                                                                                        Mode of                                                                       preparation                              A            X.sub.4 X.sub.5 M.P. (°C.)                                                                     chosen                                   ______________________________________                                         ##STR203##  H       H        51     ε.sub.1                           ##STR204##  H       H        98     α                                   ##STR205##  H       H       133     α                                   ##STR206##  H       H       178     α                                   ##STR207##  2-CH.sub.3                                                                            6-CH.sub.3                                                                            140     α                                   ##STR208##  2-CH.sub.3                                                                            H       114     ε.sub.1                           ##STR209##  H       H       120     α                                   ##STR210##  H       H       164     α                                   ##STR211##  H       H       178     α                                   ##STR212##  H       H       208     α                                   ##STR213##  H       H       192     α                                   ##STR214##  H       H       168     α                                   ##STR215##  H       H       165     ε.sub.3                           ##STR216##  H       H       104     α                                   ##STR217##  H       H       155     α                                   ##STR218##  H       H       190     α                                   ##STR219##  H       H       139     β                                    ##STR220##  H       H       98      β                                    ##STR221##  H       H       164     β                                    ##STR222##  H       H       190     β                                    ##STR223##  H       H       139     α,γ                           ##STR224##  H       H       124     α                                   ##STR225##  H       H        88     α,γ                          *4-chlorophenyl                                                                            3-CH.sub.3                                                                            5-CH.sub.3                                                                             98     α                                  ______________________________________                                         Note:-                                                                        * New compounds                                                          

I claim:
 1. A compound of the formula: ##STR226## wherein A represents2-methylphenyl, 2,6-dimethylphenyl, 4-ethylphenyl, 4-methoxyphenyl,3,4,5-trimethoxyphenyl, 4-nitrophenyl, 4-aminophenyl,4-trifluoromethylphenyl, 3-trifluoromethylphenyl or4-chloro-3-methoxyphenyl;R, X₄ and X₅ are the same or different andrepresent hydrogen or C₁₋₄ alkyl; Y represents OH or C₁₋₁₂ alkoxy; andX_(o) represents oxygen if Y is OH or represents oxygen or the --O--CH₂--CH₂ --O--group if Y is C₁₋₁₂ alkoxy; or an acid addition thereof. 2.The compound as defined in claim 1 wherein R is CH₃, X₄ and X₅ arehydrogen and X_(o) is oxygen.
 3. A pharmaceutical composition for thetreatment of hyperlipaemia comprising a therapeutically active amount ofa compound as claimed in claim 1 or a non-toxic acid-addition saltthereof, and a physiologically acceptable pharmaceutical excipient. 4.Diethylaminoethyl 2-[(4-benzoyl)-phenoxy]-2-methylpropionate. 5.Isopropyl 2-[4-(p-hydroxybenzoyl)-phenoxy]-2-methylpropionate. 6.Isopropyl 2-[4-(p-nitrobenzoyl)-phenoxy]-2-methylpropionate.